1. Field of the Invention
The present invention provides a method of treating chemical dependency in mammals and a composition therefore.
2. Discussion of the Background
Ibogaine is one of at least 12 alkaloids found in the Tabernanthe iboga shrub of West Africa. The indigenous peoples have used the drug in ritual, ordeal or initiation portions in large dosages and as a stimulant in smaller doses. One of the earliest European references to the drug was made by Professor Baillon on the Mar. 6th, 1889 session of the Linnaen Society in Paris during which he described samples obtained by Griffon de Bellay from Gabon and the French Congo.
Early isolation, and identification of ibogaine was accomplished by Dybowski and Landrin (Compt. rend. ac. sc. 133:748, 1901); Haller and Heckel (ibid. 133:850); Lambert and Heckel (ibid. 133:1236) and Landrin (Bull. sc. pharm. 11:1905).
There was little interest in the drug until Raymond-Hamet and his associates Rothlin, E. and Raymon-Hamet published the xe2x80x9cEffect of Ibogaine on the Isolated Rabbit Uterusxe2x80x9d in 1938 (Compt. rend. soc. biol. 127:592-4). Raymond-Hamet continued to study the drug for a period of 22 years, and singularly published 9 papers: Pharmacological Action of Ibogaine (Arch. intern. pharmacodynamie, 63:27-39, 1939), Two physiological Properties Common to Ibogaine And Cocaine (Compt. rend. soc. biol. 133:426-9, 1940), Ibogaine And Ephedrine (Ibid. 134:541-4, 1940), Difference Between Physiological Action of Ibogaine And That of Cocaine (Ibid. 211:285-8, 1940), Mediate And Intermediate Effects Of Ibogaine On The Intestine (Compt. rend. soc. biol. 135 176-79, 1941), Pharmacologic Antagonism Of Ibogaine (Compt. rend. 212:768-771, 1941), Some Color Reactions Of Ibogaine (Bull. soc. chim. Biol., 25:205-10, 1943), Sympathicosthenic Action Of Ibogaine On The Vessels Of the Dog""s Paw (Compt. rend 223:757-58, 1946), and Interpretation Of The Ultraviolet Absoption Curves Of Ibogaine And Tabernanthine (Ibid. 229:1359-61, 1949).
Vincent, conducted work on ibogaine in collaboration with Sero, Inhibiting Action Of Tabernanthe Iboga On Serum Cholinesterase (Compt. rend. Soc. Biol. 136:612-14, 1942). Vincent published five other papers: The Ultraviolet Absorption Spectrum Of Ibogaine (Brustier, B., Vincent D., and Sero, I., (Compt. rend., 216:909-11, 1943), Detection of Cholinesterase Inhibiting Alkaloids (Vincent, D. and Beaujard, P., Ann. pharm. franc. 3:22-26, 1945), The Cholinesterase Of The Pancreas: Its Behavior In the Presence Of Some Inhibitors In Comparison With The Cholinesterases of Serum And Brain (Vincent, D. and Lagreu, P., Bull. soc. chim. biol. 31:1043-45, 1949); and two papers, which he and Raymond-Hamet co-authored: Action Of Some Sympathicosthenic Alkaloids On the Cholinesterases (Compt. rend. soc. biol., 150:1384-1386, 1956) and On Some Pharmacological Effects Of Three Alkaloids Of Tabernanthe Iboga, Bailion: Ibogaine, Iboluteine And Tabernanthine (Compt. rend. soc. biol., 154:2223-2227, 1960).
The structure of ibogaine was investigated by Dickel et al. (J. A. C. S. 80, 123, 1958). The first total synthesis was cited by Buchi et al. (J. A. C. S., 87, 2073, 1965) and (J. A. C. S. 88, 3099, 1966).
In 1956 Salmoiraghi and Page elucidated the relation between ibogaine and serotonin (J. Pharm and expt. ther. 120 (1), 20-25, 1957.9). Contemporaneously, Schneider published three papers. The first, Potentiation Action Of Ibogaine On Morphine Analgesia was done in collaboration with Marie McArthur (Experiential 12:323-324, 1956), while the second was Neuropharmacological Studies of Ibogaine: An Indole Alkaloid With Central-Stimulant Properties (Schneider, J. A. and Sigg, E. B., Annals of N.Y. Acad, of Sciences, Vol. 66:765-776, 1957). The third was An Analysis Of the Cardiovascular Action Of Ibogaine HCL (Schneider, J. A. and Rinehard, R. K., Arch. int. pharmacodyn., 110:92-102, 1957).
The stimulant properties of ibogaine were further investigated by Chen and Bohner, (J. Pharm. and Expt. Ther., 123 (3): 212-215, 1958). Gerson and Lang published A Psychological Study Of Some Indole Alkaloids (Arch. intern. pharmacodynamie, 135:31-56, 1962).
In 1963, Bunag evaluated certain aspects of the relationship between ibogaine and Substance P (Bugag, R. D.; Walaszek, E. J. The Cardiovascular Effects of Substance P in the Chicken Ann. N.Y. Acad. Sci. 104, Part 1, 437-48, 1963).
In 1969, Naranjo reported on the effects of both ibogaine and harmine on human subjects in his paper: Psychotherapeutic Possibilities Of New Fantasy-Enhancing Drug (Clinical Toxicology, 2 (2): 209-224, June 1969).
As a doctoral thesis in 1971, Dhahir published A Comparative Study of The Toxicity Of Ibogaine And Serotonin (University Microfilm International 71-25-341, Ann Arbor, Mich.). This thesis provides an overview of much of the work accomplished with ibogaine.
Additionally, studies of interest also include: The Effects Of Some Hallucinogens On Aggressiveness Of Mice And Rats (Kostowski et al., Pharmacology 7:259-263, 1972), Cerebral Pharmacokinetics Of Tremor-Producing Harmala And Iboga Alkaloids (Zetler et al., Pharmacology 7 (40: 237-248, 1972), High Affinity 3H-Serotonin Binding To Caudate: Inhibition By Hallucinogenic And Serotonergic Drugs (Whitaker, P. and Seeman, P., Psychopharmacology 59:1-5, 1978, Biochemistry), Selective Labeling Of Serotonin Receptors by d-(3H) Lysergic Acid Diethylamide In Calf Caudate (Proc. natl. acad. sci., USA, Vol. 75, No. 12, 5783-5787, Dec. 1978, Biochemistry) and A Common Mechanism Of Lysergic Acid, Indolealkylamine And Phenthylamine Hallucinogens: Serotonergic mediation of Behavioral Effects In Rats (Sloviter, Robert et al., J. Pharm. Expt. Ther., 214 (2):231-238, 1980).
Ibogaine is an alkaloid of the formula: 
It is an intriguing structure, which combines the structural features of tryptamine, tetrahydrohavaine and indoloazepines. The total synthesis of ibogaine has been reported. See Buchi, G. et al, J. Am. Chem. Soc., 1966, 88, 2099 (1966); Rosenmund, P. et al, Chem. Ber., 108, 1871 (1975) and Huffman et al, J. Org. Chem., 50, 1460 (1985).
More recently, it was discovered that ibogaine was effective as an xe2x80x9cinterrupterxe2x80x9d of withdrawal and dependence for a variety of agents, such as heroin, cocaine, alcohol, amphetamine, caffeine and nicotine, for example. See U.S. Pat. Nos. 4,587,234, 4,857,523, 4,499,096, 5,026,697 and 5,152,994. Despite a certain and potent effect, however, studies have failed to elucidate a mechanism of action. For example, studies of the binding properties of ibogaine to a large number of neurotransmitter receptor clones has failed to detect any significant pharmacology activities that would explain its mechanism of action.
Nevertheless, administration of ibogaine has proven to be generally effective in mammals for treating chemical dependency. Such dependencies include those to substances which are as diverse as heroin, cocaine, alcohol and nicotine.
However, the effects of ibogaine are relatively short in duration and are generally not observed beyond 24 hours after administration. Thus, a need exists for an agent which is as effective as ibogaine in treating chemical dependencies, yet which is longer lasting in effect.
Accordingly, it is an object of the present invention to provide an agent which, when administered to mammals, can reduce craving for addictive substances therein.
It is, moreover, an object of the present invention to provide an agent for treating chemical dependency in mammals which is longer acting than ibogaine on the mammalian host.
It is also an object of the present invention to provide a pharmaceutical composition for reducing craving for additive substances in mammals.
Further, it is also an object of the present invention to provide a method of treating chemical dependency in a mammal, which entails administering to a mammal in need thereof an amount of essentially noribogaine or a hydrolyzable derivative thereof.
These advantages and others are provided by an essentially pure noribogaine compound having the formula: 
wherein R is hydrogen or a hydrolyzable group of the formula: 
wherein X is an unsubstituted C1-C12 group or a C1-C12 group substituted by lower alkyl or lower alkoxy groups, wherein the noribogaine having the hydrolyzable group hydrolyzes in vivo to form 12-hydroxy ibogamine.